New thiazolobenzodiazepine compounds and methods for their production

ABSTRACT

5,10-DIHYDRO - 3 - (ARYL)THIAZOLO (3,2-B) (2,4) BENZODIAZEPINES, IN WHICH THE 3-ARYL GROUP IS PHENYL, HYDROXYPHENYL, DIHYDROXYPHENYL, (LOWER ALKOXY)PHENYL, HYDROXYPHENYL, PHENYL, TOLYL, XYLYL, 2-THIENYL, OR 2-FURYL; ACID-ADDITION SALTS THEREOF; AND THEIR PRODUCTION BY REACTING 1,2,4,5-TETRAHYDRO-3H-BENZO (2,4) DIAZEPINE-3-THIONE WITH AN APPROPRIATELY SUBSTITUTED HALOMETHYL ARYL KETONE. THE COMPOUNDS OF THE INVENTION ARE USEFUL AS INHIBITORS OF BLOOD PLATELET AGGREGATION.

United States Patent 3,560,515 NEW THIAZOLOBENZODIAZEPINE COMPOUNDS AND METHODS FOR THEIR PRODUCTION Edward F. Elslager and Donald F. Worth, Ann Arbor, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Filed Aug. 5, 1968, Ser. No. 750,012 Int. Cl. C07d 99/06 U.S. Cl. 260-306.7 7 Claims ABSTRACT OF THE DISCLOSURE 5,1O-dihydro 3 (aryl)thiazolo[3,2-b] [2,4]benzodiazepines, in which the 3-aryl group is phenyl, hydroxyphenyl, dihydroxyphenyl, (lower alkoxy)phenyl, di(lower alkoxy) pheny-l, tolyl, xylyl, 2-thienyl, or Z-furyl; acid-addition salts thereof; and their production by reacting l,2,4,5-tetrahydro-3H-benz-o[2,'4]diazepine-3-thione with an appropriately substituted halomethyl aryl ketone. The compounds of the invention are useful as inhibitors of blood platelet aggregation.

SUMMARY AND DETAILED DESCRIPTION The present invention relates to new thiaz'olobenzodiazepine compounds that are useful as pharmacological agents and to methods for their production. More particularly, the invention relates to new 5, l0-dihydro-3-(aryl) thiazolo[3,2-b] [2,4]benZodiazepine compounds having in free base form the formula Tit with a halomethyl aryl ketone compound having the formula III where X is chlorine or bromine and Ar is phenyl, hydroxyphenyl, dihydroxy-phenyl, acyloxyphenyl, diacyloxyphenyl, (lower alkoxy)phenyl, di(lower alkoxy)phenyl, tolyl, xylyl, Z-thienyl, or Z-furyl. The reaction is advantageously carried out in an unreactive solvent medium. Suitable solvents include aromatic hydrocarbons, such as benzene, toluene, and xylene; tertiary amides, such as N,N-

Patented Feb. 2, 1971 dimethylformamide, N,N dimethylacetamide, and N methyl-Z-pyrrolidinone; and ethers, such as Z-methoxyethanol, dimethoxyethane, and diethylene glycol dimethyl ether; as well as mixtures of these. A preferred solvent is Z-methoxyethanol. The reaction is best carried out at an elevated temperature, which may range from to 200 C. A preferred temperature is one between and C. At the preferred temperature, the react-ion is normally complete after about 15 hours, although shorter or longer reaction periods may also be used, ranging from 15 minutes to 24 hours. It is preferable to employ equivalent amounts of 1,2,4,5-tetrahydro-3H-benzo[2,4ldiazepine-3- thione and the halomethyl aryl ketone, although a slight to moderate excess of either is not harmful.

The product of the reaction is initially obtained in hydrochloride or hydrobromide salt form, depending upon whether a chloromethyl or a bromomethyl aryl ketone is used as one of the reactants. The product may be isolated directly in this salt form or it may be converted to the free base form by appropriate adjustment of the pH of the reaction mixture.

When Ar in Formula III above is acyloxyphenyl or diacyloxyphenyl, the nature of the acyl group is not critical, because during the course of the reaction in the preferred Z-methoxyethanol solvent, the acyl group is removed to give a thiazolobenzodiazepine product of Formula I in which Ar is hydroxyphenyl or dihydroxyphenyl. Thus, the acyl group may be alkanoyl, such as acetyl, or it may be aroy l, such as benzoyl, and it may be substituted one or more times with a substituent that will not interfere with the reaction, such as lower alkyl, halogen, and nitro.

l,2,4,5-tetrahydro 3H benzo[2,4]diazepine-3-thione, which is used as one of the starting materials in the foregoing process, is prepared by first reacting o-xylene-u,ot'-

diamine with carbon disulfide and then heating the [o- (aminomethyl)benzyl]dithiocarbamic acid intermediate product at an elevated temperature (HO-130 C.) in a suitable solvent medium, such as 2-methoxyethanol, whereby hydrogen sulfide is evolved and intramolecular cyclization occurs to give the desired l,2,4,5-tetrahydro-3H- benzo[2,4]diazepine-3-thione.

The halomethyl aryl ketone starting materials having Formula III above are, as a class, known to the art. Previously unreported members of the class can be prepared by bromination or chlorination of the appropriate methyl aryl ketone, as illustrated in greater detail hereinafter.

The free base thiazolobenzod-iazepine compounds of the invention having Formula I above form acid-addition salts with any of a variety of inorganic and organic acids. Pharmaceutically-acceptable acid-addition salts can be obtained directly from the reaction described above or by reacting one of the free base compounds With an acid such as hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, and pamoic acids. The free bases and salt forms are interconvertible by adjustment of the pH. They ditfer in certain physical properties, such as solubility in polar solvents, but, in general, are otherwise equivalent for the purposes of the invention.

The compounds of the invention, in free base and acidaddition salt form, are new chemical compounds useful as pharmacological agents that are active in inhibiting blood platelet aggregation. Their activity in this regard can be demonstrated and quantitatively measured in a standard in vitro test as follows. Platelet rich plasma is prepared by centrifuging rabbit blood that has been mixed with one-tenth its volume of 3.8% aqueous sodium citrate. The platelet rich plasma is then added to an aqueous tris (hydroxymethyl)aminornethane buffer solution (pH 7.2) in Klett tubes, to which has been added either calcium 3 (1.0 ,umoles/ml.) alone, in the case of control tubes, or calcium (1.0 moles/ml.) and one of the test compounds at varying molar concentrations. A reading of the optical density is immediately taken for each of the tubes. To each tube is then added adenosine diphosphate (1.0,ug./

disulfide in 150 ml. of ethanol while the temperature is maintained below 30 C. The resulting mixture is stirred at room temperature for 2.5 hours and then filtered to isolate the solid precipitate of [o-(aminomethyl)benzyl]- dithiocarbamic acid; M.P. 300 C. This intermediate ml.), which is known to cause aggregation of blood plateproduct (180 g.) is added to 500 ml. of 2-methoxyethanol, lets and hence a consequent decrease in optical density, and the resulting mixture is heated under reflux for one and the tubes are shaken mechanically on a rotating table hour or until no more hydrogen sulfide is evolved. The for eight minutes, when an optical density reading is again reaction mixture is then cooled, and the solid 1,2,4,5- taken for each tube. tetrahydro 3H benzo[2,4]diazepine 3 thione that The readings for the control tubes are compared with precipitates is isolated and dried; M.P. 290 C, (with those hfor the tubes containing the test compound, and decomposition). the in ibition of aggregation caused by the test compound is calculated as the percentage difference between the de- EXAMPLE 2 creasein optical density in the two sets of tubes. Thus, Utilizing the procedure described in Example 1 above if the decrease in optical density in the test compound the following thiazolobenzodiazepine compounds are obtubes is of the decrease in the control tubes, the tained from the reaction of the indicated amount of 1,2,4,5- test compound is considered to cause an 80% inhibition tetrahydro 3H benzo[2,4]diazepine-3-thione (referred of aggregation. to below as thione) and the designated halomethyl aryl The results obtained in the foregoing test procedure 20 ketone: for some representative compounds of the present inven- (a) o-(5,10 dihydrothiaz0lo[3,2-b] [2,4]benzodiazetion are summarized in the following table. pin 3 yl)phenol monohydrobromide, M.P. 273 C. fol- Inhibition of Molar latelet coneenaggregation Compound tration percent 5,10-dihydro-3-phenylthiazol0[3,2b][2,41bcnzodiazepine 10- 2 79, 57 o-(5,l0-dihydrothiazolo[3,2-b][2,4]benzodiazepin-il-yl) phenol 5 XIO- 73 5,ggngggofi-(o-1neth0xyphenyl)thiaz0lo[3,2-b][2,41benz0- 5 l0- 2 100, 80, 73 5,l0-diliydro-3-(2,4-xylyl)thiazolo[3,2-b][2,4]benzodiazepino 5 l0' 85 B-(Z-furyl)-5,10-dihydrothlazoI0[3,2-l)][2,4]benzodiazepine 5X10-5 G2 6,lO-dihydro 3-(2-thienyl)thiazololB,2-b][2,4]bcnzodiazepine 5Xl0- 68 1 Tested as the hydrobromido salt. 2 Separate values obtained in separate, individual experiments. 3 Tested as tho hydrochloride salt.

The preferred compounds of the invention, by virtue of lowing crystallization from acetonitrile; from 3.7 g. of their high degree of activity in inhibiting blood platelet thione and 4.8 g. of a-bromo-o-hydroxyacetophenone aggregation, are 5,10-dihydro-3-(o-methoxyphenyl)thiabenzoate ester in 450 ml. of 2-methoxyethanol. zolo[3,2-b][2,41benzodiazepine and pharmaceutically-ac- (b) 4-(5,10 dihydrothiazolo[3,2-b] [2,41benzodiazeceptable salts thereof. pin 3 yl)pyrocatechol monohydrochloride, M.P. 258- The invention is illustrated by the following examples. 259 C. (2-methoxyethanol); from 3.7 g. of thione and 3.8 g. of u-chloro 3,4-dihydroxyacetophenone in 150 ml. EXAMPLE 1 of 2-methoxyethanol.

A solution of 12.4 g. of ot-bromoacetophenone in 100 5,10 y 3 YP Y ml. of 2-methoxyethanol is added in portions over a per- P monohydfobfomide, iod of five minutes to a solution of 10.0 g. of 1,2,4,5- from of thione and of wbromotetrahydro-3H-benzo[2,4]diazepine 3 thione in 1000 o-methoxyacetophenone in 600 ml. of Z-methoxyethanol. ml. of boiling 2-methoxyethanol, and the resulting mixture (d) 5,10 dihydro 3 (m-methoxyphenyl)th1azolo is heated under reflux for 2.5 hours. The reaction mixture [2,4lbenlodialepine monohydfobmmlde, is then evaporated under reduced pressure to give a solid 252-254 C. (water); from 3.0 g. of thione and 3.7 g. residue of 5,10-dihydro-3-phe-nylthiazolo[3,2-b][2,4]benzoof u-bromo-m-methoxyacetophenone in 300 ml. of 2- diazepine monohydrobromide, which is isolated, washed methoXy with ethanol, and dried; M.P. 256257 c. dihydro tpyp yll i The above product is obtained in free base form by the [3, [2,4]benz0 i Z p1 mon hy ro r mlde, M.P. following procedure. The hydrobromide salt is dissolved 244 C. (water); from 3.0 g. of thione and 3.7 g. of ozin aqueous ethanol, and the resulting solution is made bromo-p-methoxyacetophenone in 300 ml. of Z-methoxybasic with aqueous sodium hydroxide, The basic mixture ethanol. is then diluted with an equal volume of water, and the 3 dimethoXyphenyl) sllo'dlhydrothlazob free base 5,10-dihydro 3 phenylthiazolo[3,2-b][2,4]- l p monohydfobromidel benzodiazepine that precipitates is isolated and dried. 248 C- (Wat f -0 gf h n and 4.2 g. of a- 5,1() dih d 3 h 1thi 1 [3,2 b] [2,4]ben bromo-2,S-dihydroxyacetophenone in 300 ml. of 2-methdiazepine monocitrate is obtained by adding a solution of oxyethanol.

2.78 g. of the free base in methanol to a solution of 1.92 Y 3 Y YD g. of citric acid in methanol and evaporating the resulting benzodiazepine monohydrochloride, M.P. 259-260 C. mixture to dryness under reduced pressure. (2-p 0pan0l); fr m 2.9 g. of thione and 3.0 g. of on- 5,10 dihydro 3 phenylthiazolo[3,2-b] [2,4]benzochloro-2,4-dimethylacetophenone in 200 ml. of 2-methdiazepine monoacetate is obtained by treating a solution oxyethanol. of 5.56 g. of the free base in methanol with 1.2 g. of (h) 3 (2- furyl) 5,10 dihydrothiazolo[3,2-b][2,4] glacial acetic acid and evaporating the resulting mixture z dia ep ne monohydrobromide, M.P. 207-209 C. to dryness u der redu ed ur (methanolethyl acetate); from 3.6 g. of thione and 3.8 g.

The 1,2,4,5 tetrahydro 3H beIlZO[2,4]diaZepineof bromomethyl 2-fury1 ketone in 150 m1. of 2-methoxy- 3-thione starting material is obtained as follows. A soluethanol. tion of 154 g. of o-xylene-a,a'-diamine in 800 ml. of (i) 5,10-dihydro- 3 (2-thienyl)thiazolo[3,2-b][2,4] ethanol is added to a stirred solution of 136 ml. of carbon fi zodiazepine monohydrobromide, M.P. 232233 C.

(ethanolether) from 3.6 g. of thione and 4.1 g. of brornomethyl Z-thienyl ketone in 100 ml. of Z-methoxyethanol.

EXAMPLE 3 Utilizing the procedure of Example 1 above, the following thiazolobenzodiazepine compounds are obtained from the reaction of equimolar amounts of 1,2,4,5-tetrahydro- 3H-benzo[2,4]diazepine-3-thione and the halomethyl aryl ketone designated below in Z-methoxyethanol:

(a) 3 (p ethoxyphenyl) 5,10 dihydrothiazolo [3,2-b] [2,4]benzodiazepine monohydrochloride; from achloro-p-ethoxyacetophenone.

(b) 3 (2,5 diethoxyphenyl) 5,10-dihydrothia2olo [3,2-b] [2,4]benzodiazepine monohydrobromide; from abromo-2,S-diethoxyacetophenone.

(c) 5,10 dihydro 3 (m-tolyl)thiozolo[3,2-b] [2,4] benzodiazepine monohydrochloride; from :x-chloro-mmethylacetophenone.

(d) 5,10 dihydro 3 (o-tolyl)thiazolo[3,2-b][2,4] benzodiazepine monohydrobromide; from a-bromo-omethylacetophenone.

The preparation of the various halomethyl aryl ketone starting materials that are required for the production of the compounds of this and preceding examples can be illustrated by the preparation of a-bromo-o-methoxyacetophenone and a-chloro-m-methoxyacetophenone, respectively, as follows:

(1) a-Bromo-o-methoxyacetophenone.-To a stirred solution of 50 g. of o-methoxyacetophenone in 500 ml. of ether is added dropwise over a period of ten minutes 53 g. of bromine while the temperature is maintained below 30 C. The resulting mixture is stirred at room temperature for 30 minutes and is then evaporated to dryness to give a solid residue of u-bromo-o-methoxyacetophenone, M.P. 4044 C. following crystallization from cyclohexane.

(2) a-Chloro-m-methylacetophenone.-A solution of 13.5 g. of sulfuryl chloride in 100 ml. of dry ether is added dropwise to a stirred solution of 13.4 g. of mmethylacetophenone in 150 ml. of dry ether while the temperature is maintained below 30 C. The resulting solution is stirred at room temperature for one hour and is then evaporated to dryness to give a residue of ot-chlorom-methylacetophenone, suitable for use without further purification.

We claim:

1. A member of the class consisting of 5,10-dihydro- 3 (aryl)thiazolo[3,2-b] [2,4]benzodiazepine compounds having in free base form the formula and pharmaceutically-acceptable salts thereof; where Ar is a member of the class consisting of phenyl, hydroxyphenyl, dihydroxyphenyl, (lower alkoxy)phenyl, di(lowe1' alkoxy)phenyl, tolyl, xylyl, 2-thienyl, and 2-furyl.

2. Pharmaceutically-acceptable acid-addition salts of 5,10-dihydro 3 (aryl)thiazo1o[3,2-b][2,4]benzodiazepine compounds as defined in claim 1.

3. A compound according to claim 2 which is 5,10- dihydro 3 (o-methoxyphenyl)thiazolo[3,2-b] [2,4]benzodiazepine monohydrobromide.

4. A compound according to claim 2 which is 5,10- dihydro 3 phenylthiazolo[3,2-b][2,4]benzodiazepine monohydrobromide.

5. A compound according to claim 2 which is o-(5,l0- dihydrothiazolo[3,2-b] [2,4]benzodiazepin 3 yl) phenol monohydrobromide.

6. A compound according to claim 2 which is 5,10- dihydro 3 (m methoxyphenyl)thiazolo[3,2-b][2,4] benzodiazepine monohydrobromide.

7. A compound according to claim 2 which is 3-(2- furyl) 5,10 dihydrothiazolo[3,2-b] [2,4]benzodiazepine monohydrobromide.

References Cited UNITED STATES PATENTS 9/1964 Szmuszkovicz 260306.7 12/1965 Walker 260-306] ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner 

